1. Field of the Invention
The present invention relates to methods and compositions for treating fibrotic tissue disorders in human patients.
2. Description of the Prior Art
Tissue fibrosis, characterized by excessive deposition of connective tissue components (most notably collagen) is the major pathological feature in various clinical conditions. The collagen deposition can take place in various internal organs, as in pulmonary fibrosis or liver cirrhosis. Skin is also commonly affected by fibrotic processes, and dermal fibrosis is the clinical pathological hallmark of several acquired and heritable cutaneous disorders.
In most cases, fibrosis is a reactive process, and several different factors can apparently modulate the pathways leading to tissue fibrosis. Such factors, largely elaborated by the inflammatory tissue reaction, include the local expansion of fibroblast subpopulations, immune modulation of the synthetic functions of fibroblasts, and altered regulation of various metabolic reactions governing the biosynthesis and degradation of the connective tissue components. Thus, the net accumulation of collagen in components. Thus, the net accumulation of collagen in fibrosis is a result of imbalance between the factors leading to production and deposition or degradation and removal of collagen.
Although various modalities have been utilized to treat fibrotic diseases and disorders, none of these treatments have been particularly effective because they generally are directed to the symptoms of the disorders but not at the underlying pathology, namely, the imbalance in the metabolic factors regulating production, deposition, degradation and removal of collagen and other connective tissue components. Thus, for example, while topical corticosteroids have been used with some degree of success in treating the early, inflammatory stage of cutaneous keloid formation, such steroid therapy has little or no effect on the later, fibrotic stage when the keloids are actually formed as a result of excess collagen production.
It has been discovered in recent years, however, that activated T-lymphocytes and monocytes/macrophages can effective modulate several fibroblast functions through the release of soluble macromolecular factors, collectively categorized as lymphokines (for the factors released by lymphocytes) and monkines (for the factors released by monocytes such as macrophages). Among the fibroblast functions modulated by these lymphokines and monokines is the production of fibrosis-forming collagen. See, e.g., Duncan, M. R. et al., J. Invest. Dermatol., 83:377 (1984). In 1985, we identified gamma-interferon as the lumphokine an d beta-interferon as the monokine responsible for inhibition of fibroblast collagen production as well as inhibition of late, but not early, fibroblast proliferation. Duncan, M. R. and Berman, B., J. Exp. Med., 162:516-27 (1985).
A number of researchers subsequently studied the effects of gamma-interferon, principally, on collagen production in vitro or in animal models such as mice. E.g., Carlo-Stella et al., Blood, 70:1014-19 (1987); Granstein et al., J. Clin. Invest., 79:11254-58 (1987); Sharpe, Med Hypoth., 22:415-19 (1987) Czaja et al., J. Biol. Chem., 262;13348-51 (1987). Some of these researchers suggested that gamma-interferon might be useful in treating fibrotic disorders, but none have conducted published clinical trials with any interferon, nor indicated any specific method for treatment of fibrotic disorders with interferons.
In a paper first published in full in 1987, we disclosed our discovery that a reduced-collagen-producing phenotype in cultured scleroderma fibroblasts persisted after short term exposure to interferons, whether alpha-, beta- or gamma-. Duncan, M. R. and Berman, B., J. Clin. Invest., 79:1318-24 (1987). Notwithstanding that discovery, which was based solely on in vitro data, it was not at all clear whether or which types of interferons would be useful in the treatment of fibrotic tissue disorders in vivo, particularly disorders such as cutaneous keloid formation, scleroderma, progressive systemic sclerosis, and the like, where mere restoration of normal fibroblast collagen production levels may prevent further excess collagen deposition, but will not remove or degrade the fibrotic lesions already formed. Moreover, because of the complexity of the interacting metabolic factors relating to connective tissue matrix formation and degradation, the fact that interferons appeared to cause a persistent inhibition of fibroblast collagen production in vitro by no means proved that a similar effect would be observed in vivo.
Hence, notwithstanding the foregoing discoveries, there has been no method disclosed in the prior art for treating fibrotic tissue disorders in humans in a safe and effective manner to inhibit further fibrotic tissue formation and to reduce or remove entirely already-formed fibrotic lesions.